title: The interaction of antipsychotic drugs with lipids and subsequent lipid reorganization investigated using biophysical methods.
abstract: The interaction of antipsychotic drugs (AP) with lipids and the subsequent lipid reorganization on model membranes was assessed using a combination of several complementary biophysical approaches (calorimetry, plasmon resonance, fluorescence microscopy, X-ray diffraction and molecular modeling). The effect of haloperidol (HAL), risperidone (RIS), and 9-OH-risperidone (9-OH-RIS) was examined on single lipid and mixtures comprising lipids of biological origin. All APs interact with lipids and induced membrane reorganization. APs showed higher affinity for sphingomyelin than for phosphatidylcholine. Cholesterol increased AP affinity for the lipid bilayer and led to the following AP ranking regarding affinity and structural changes: RIS >9-OH-RIS >HAL. Liquid-ordered domain formation and bilayer thickness were differentially altered by AP addition. Docking calculations helped understanding the observed differences between the APs and offer a representation of their conformation in the lipid bilayer. Present results indicate that AP drugs may change membrane compartmentalization which could differentially modulate the signaling cascade of the dopamine D2 receptor for which APs are ligands.
authors.affiliation: Université Pierre et Marie Curie-Paris 6, UMRS 7203 CNRS-ENS, Laboratoire des BioMolécules, 4, place Jussieu, 75252 Paris cedex 05, France.
authors.forename: Isabel
authors.initials: I
authors.lastname: Alves
authors.forename: Galya
authors.initials: G
authors.lastname: Staneva
authors.forename: Cedric
authors.initials: C
authors.lastname: Tessier
authors.forename: Gilmar F
authors.initials: GF
authors.lastname: Salgado
authors.forename: Philippe
authors.initials: P
authors.lastname: Nuss
mesh_terms: D015060:1,2-Dipalmitoylphosphatidylcholine / Q000737:chemistry; D014150:Antipsychotic Agents / Q000737:chemistry* / Q000494:pharmacology; D002152:Calorimetry, Differential Scanning; D002462:Cell Membrane / Q000737:chemistry* / Q000187:drug effects; D002784:Cholesterol / Q000737:chemistry; D018492:Dopamine Antagonists / Q000737:chemistry / Q000494:pharmacology; D065127:Dopamine D2 Receptor Antagonists; D006220:Haloperidol / Q000737:chemistry / Q000494:pharmacology; D007555:Isoxazoles / Q000737:chemistry / Q000494:pharmacology; D008563:Membrane Lipids / Q000737:chemistry*; D008567:Membranes, Artificial; D008856:Microscopy, Fluorescence; D008958:Models, Molecular; D008968:Molecular Conformation; D015394:Molecular Structure; D000068882:Paliperidone Palmitate; D010713:Phosphatidylcholines / Q000737:chemistry; D011743:Pyrimidines / Q000737:chemistry / Q000494:pharmacology; D017448:Receptors, Dopamine D2 / Q000737:chemistry; D018967:Risperidone / Q000737:chemistry / Q000494:pharmacology; D013109:Sphingomyelins / Q000737:chemistry; D013329:Structure-Activity Relationship; D020349:Surface Plasmon Resonance; D014961:X-Ray Diffraction
chemical_list: D014150:Antipsychotic Agents; D018492:Dopamine Antagonists; D065127:Dopamine D2 Receptor Antagonists; D007555:Isoxazoles; D008563:Membrane Lipids; D008567:Membranes, Artificial; D010713:Phosphatidylcholines; D011743:Pyrimidines; D017448:Receptors, Dopamine D2; D013109:Sphingomyelins; D015060:1,2-Dipalmitoylphosphatidylcholine; D002784:Cholesterol; D006220:Haloperidol; D018967:Risperidone; D000068882:Paliperidone Palmitate